Project Summary/Abstract Neurological and psychiatric disorders, including substance abuse and addiction, exert a devastating personal and economic toll on patients, families, caregivers, and society. This is in part due to our failures in developing effective medications, which in turn to the drug discovery platforms that are often not relevant to target diseases. Recent development of induced pluripotent stem cells (iPSCs) from humans makes it possible to screen and validate candidate compounds on human nerve cells, including those from patients, thus potentially increasing the success rate and speeding up the pace in CNS drug development. BrainXell, Inc. has pioneered in developing human patient neural cell-based platforms for CNS drug discovery. We are able to produce large quantities of highly enriched, functionally specialized neurons of consistent quality from human iPSCs through our platform technology of directed neural differentiation and expansion of committed progenitors. However, iPSC-derived neurons are immature, comparable to those at the fetal stage, which makes it difficult for presentation of disease phenotypes and for high-throughput screening (HTS) for drug leads intended for those whose brains are fully mature. The goal of this Phase I SBIR project is to uncover molecules that accelerate the maturation of cortical glutamatergic and midbrain dopaminergic neurons and to formulate cocktails that yield mature neurons within a week of plating their progenitors. We have engineered a human iPSC reporter line with the fusion of nanoluciferase (Nluc) with synaptophysin (SYP), a synaptic vesicle glycoprotein expressed in virtually all mature neurons to enable and simplify the screening of small molecules for accelerating neuronal maturation. Formulation of an effective cocktail for rapidly generating human mature neurons will remove the major roadblock in establishing human patient neuron-based HTS for CNS drug development.